Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al. N. Engl. J. Med. 330:811–815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release of norepinephrine by neurons upon administration of nicotine has been reported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release of serotonin by neurons upon administration of nicotine has been reported by Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release of glutamate by neurons upon administration of nicotine has been reported by Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain disorders. See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993); Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, Decina et al., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry 21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984); Onaivi et al., Life Sci. 54(3): 193 (1994); Tripathi et al., JPET 221:91–96 (1982) and Hamon, Trends in Pharmacol. Res. 15:36.
Various nicotinic compounds have been reported as being useful for treating a wide variety of conditions and disorders. See, for example, Williams et al. DN&P 7 (4): 205–227 (1994), Arneric et al., CNS Drug Rev. 1 (1): 1–26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5 (1): 79–100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med. Chem. 40 (28): 4169–4194 (1997), Bannon et al., Science 279:77–80 (1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No. 5,604,231 to Smith et al. and U.S. Pat. No. 5,616,716 to Dull et al. Nicotinic compounds are reported as being particularly useful for treating a wide variety of Central Nervous System (CNS) disorders.
CNS disorders are a category of neurological disorders that can arise from genetic predispositions or environmental factors, such as infection, trauma, and drug use. In some instances, the etiology of particular CNS disorders is unknown. CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to cholinergic, dopaminergic, adrenergic and/or serotonergic deficiencies. CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Lewy Body dementia, Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia, mile cognitive impairment and Tourette's syndrome.
It, therefore, is desirable to provide a useful method for the prevention and treatment of a condition or disorder by administering a nicotinic compound to a subject susceptible to or suffering from such a malady. It is highly beneficial to provide individuals suffering from certain disorders (e.g., CNS disorders) with interruption or reduction in the severity of the symptoms of those disorders by the administration of a pharmaceutical composition that contains an active ingredient or a pro-drug form or an N-oxide having nicotinic pharmacology. It is also desirable to provide a pharmaceutical composition incorporating a compound that when administered and metabolized interacts with nicotinic receptors, such as those which have the potential to affect the functioning of the central nervous system (CNS), but that when employed in an amount sufficient to affect the functioning of the central nervous system (CNS), does not significantly affect those receptor subtypes that have the potential to induce undesirable side effects (e.g., appreciable activity at skeletal muscle and ganglia sites).